The proposed research will examine the structure and functional properties of two proteins, the cholinergic-nicotinic receptor and acetylcholinesterase, which govern excitability phenomena at the postjunctional site in the nicotinic synapse. Pharmacologic manipulation such as inhibition of acetylcholinesterase drastically modifies function suggesting a precise coordination between these two proteins which is dependent on their structural disposition within the synapse. To understand the molecular details of synaptic transmissson and the influence of drugs such as acetylcholinesterase inhibitors and nicotinic agonists and antagonists on this process, a knowledge of the detailed structure of the macromolecules is sought. Functional aspects of the macromolecules are probed primarily through complexation of pharmacologically active ligands with the isolated and purified macromolecules. Through physical-chemical approaches, we will examine ligand (drug) specificity and the conformational changes that accompany ligand association. Fast kinetic monitoring, fluorescence and magnetic resonance spectroscopy are employed for this purpose. These results will be correlated with information on the structure of the macromolecules obtained from fluorescence energy transfer, fluorescence polarization, affinity labeling, peptide mapping and analysis of subunit interactions.